Standard local treatment of aggressive squamous cell carcinomas (SCC) of the skin continues to be plaqued with primary disease recurrence and second primary tumors in most patients afflicted with these cancers. In addition to substantial mortality rates, cosmetic, psychologic and functional impairment are frequent and devastating sequelae of aggressive skin cancers and the required definitive local therapy. Using our prospective skin cancer database, four clinical-histologic criteria (depth of invasion, perineural invasion, lesion size, regional metastases) define a population of patients at greater than 70% risk of local, and/or regional recurrence after definitive local/regional therapy. Second primary tumors (SPTs) occur at a rate approximating 6% per year. Single-agent therapy with retinoic acid or alpha-interferon have limited activity in the therapy of advanced solid tumors. However, both of these agents are known to possess antiproliferative, differentiative, anti-angiogenic and immunomodulatory properties; probably exerting these effects through separate molecular mechanisms. Ongoing mechanistic studies have indicated some potentially important anticancer interaction sof retinoid-interferon combinations. In vitro studies of retinoid-interferon-alpha combinations indicate a synergistic interaction in the induction of interferon-stimulated gene factor and several interferon inducible enzymes (e.g., 2'-5' oligoadenylate synthetase) and programmed-cell death. In vivo studies have found synergistic inhibition of experimental tumor induced angiogenesis. Clinical studies include two recent phase II trials of 13-cis retinoic acid (13-cRA) in combination with alpha-interferon which have reported major responses rates of 50% and 68% in advanced skin SCC. Based on the substantial preclinical and clinical experience, we now propose an adjuvant chemoprevention study using these agents for six months in patients with aggressive squamous carcinoma of the skin treated with standard surgery and radiation therapy. This chemopreventive and therapeutic approach is designed to decrease the development of primary disease recurrence (local, regional and distant) as well as SPTs, in a controlled, randomized trial. A number of correlative laboratory and mechanistic studies aimed at understanding several major aspects of the mechanisms of action of retinoids and interferon are included within this clinical trial. In addition, we will obtain, through self-administered questionnaires, outcome information on these SCC patients relative to emotional well-being, quality of life, cognitive functioning, and pain in order to develop longitudinal profiles of these outcome parameters. A total of 90 patients, meeting these high risk criteria, will be required for the study with a minimum follow-up of three years.